Liver cancer—hepatocellular carcinoma (HCC)—is one of the leading causes of cancer-related deaths worldwide, particularly in China and Africa. HCCs are most often associated with chronic hepatitis B virus (HBV) infection and are more common in men than in women. However, women with HCC tend to survive longer than men, suggesting that gender-specific differences influence therapeutic response. The most common treatments for HCC include surgery, liver transplantation, chemotherapy, and targeted therapies, including immunotherapy with interferon-α (IFN-α). The response to IFN-α treatment is modest in unselected patient populations but may be effective in specific subsets of patients. Determining which patients will benefit from IFN-α treatment could significantly improve patient outcome. Now, Hou and colleagues show that expression of retinoic acid–inducible gene-I (RIG-I) strongly correlates with survival and response to IFN-α treatment.

The RIG-I protein is a human sensor of viral RNA that normally functions to prevent infection. In cell culture and mouse models of HCC, RIG-I knockdown conferred resistance to IFN-α treatment, whereas RIG-I knockout enhanced HCC tumorigenesis in both male and female mice. These results show that HCC gender disparity was abolished in the context of RIG-I deficiency, suggesting that RIG-I may be responsible for the sex-specific differences in HCC incidence and therapeutic response. Consistent with this hypothesis, RIG-I levels were lower in male as compared with female liver tissue in both mice and humans.

These findings suggest that RIG-I expression may be an effective biomarker to select patients that will benefit from IFN-α treatment. Going forward, it will be important to determine the level of RIG-I positivity required for a significant response to IFN-α. Because the patient population in this study included a high frequency of HBV infections, it remains to be determined whether RIG-I will influence IFN-α response in non–HBV-associated HCCs or other diseases treated with IFN-α. Nevertheless, RIG-I appears to be a much-needed harbinger for therapeutic benefit in HCC.